1. Field of the Invention
It is known that cancer chemotherapeutic agents available at the present time produce undesirable side effects on account of their low selectivity, that limit the dose that can be applied or may even lead to a discontinuation of the treatment. The aim must therefore be to utilise genetic and phenotype differences between normal and malignant cells in order to achieve a higher selectivity.
2. Description of the Related Art
For this purpose prodrugs may be used that are either acid-catalysed by the pH value reduced by 1 to 2 units in tumour cells or that can be split within the scope of the ADEPT concept (antibody directed enzyme prodrug therapy), which is based on the utilisation of conjugates of glycohydrolases and monoclonal antibodies that bind to tumour-associated antigens [see Pharmacology & Therapeutics 83, 67–123, (1999); J. Biol. Chem. 272, 15804–15816, (1997); J. Med. Chem. 41, 1507–1512, (1998); Bioconjug. Chem. 98, 255–259, (1998); Cancer Immunol. Immunother. 44, 305–315, (1997)]. In this connection cytotoxic compounds are used that are detoxified by conversion into enzymatically splitable derivatives (prodrugs). The enzyme-antibody conjugates are selectively present, after their administration, on the surface of the cancer cells and split the prodrugs only in the tumour, with the release of the cytotoxic compound.
As cytotoxic compounds there have inter alia already been used derivatives of the seco-CI analogue of the natural substance CC-1065 that have been converted, inter alia as galactocides, into corresponding prodrugs. Glycohydrolases inter alia have been used for the antibody-enzyme conjugates [see Angew. Chem. 108, 2840–2842, (1996); Angew. Chem. Int. Ed. Engl. 35, 2674–2677, (1996)]. Essential criteria for the successful use of prodrugs within the framework of the ADEPT concept are the low toxicity of the prodrugs, a very high cytotoxicity of the underlying cytostatic agent, and a rapid splitting of the prodrug in the presence of the corresponding enzyme.
It is furthermore known that malignant cells exhibit an enhanced glycolysis and thus lactate production compared to normal tissue, and that the pH in the tumour tissue can be lowered by intravenously applied glucose [see S. Tanneberger, Experimentelle und klinische Tumorchemotherapie; Allgemeine Tumorchemotherapie; G. Fischer Verlag, Stuttgart/New York 1980; Naturwiss. 46, 2 (1959); Cancer Res. 42, 1498 (1982); 42, 1505 (1982); 49, 4373 (1989)].
It is also known that numerous glycohydrolases in a slightly acidic medium have a higher activity than at pH 7.4. Such glycohydrolases may also be bound to monoclonal antibodies that bind selectively to specific tumour-associated antigens on the membrane of malignant cells [see Pharmacology & Therapeutics 83, 67 (1999)].
In the past attempts have been made to utilise these differences in the pH value between normal tissue and tumour tissue for a selective tumour therapy [see Cancer Res. 49, 4179, (1989); Liebigs Ann. Chem. 847 (1987); Tetrahedron Lett. 22, 239, (1981); Angew. Chem. 102, 812, (1990); Liebigs Ann. Chem. 151, (1990)]. The acid-labile non-toxic prodrugs used for this purpose that are obtained from alkylating compounds have however proved not to be sufficiently acid-labile that they can be split selectively in the tumour tissue to form an active cytocidal agent.
Attempts have also been made to convert cytotoxic compounds by derivatisation into enzymatically splitable prodrugs having a reduced toxicity. With the previously synthesised compounds the problem arose that either the differences in the cytotoxicity of the prodrug and the underlying drug were not sufficient, and/or the drug was not sufficiently effective [see Angew. Chem. 108, 2840, (1996)].
In contrast to this the acid-catalysed prodrugs or prodrugs enzymatically splitable preferably with glycohydrolases proposed in the present invention that are obtained from 6-hydroxy-2,3-dihydro-1H-indolene, 5-hydroxy-1,2-dihydro-3H-pyrrolo[3,2-e]indolene and 5-hydroxy-1,2-dihydro-3H-benzo[e]indolene as well as from 6-hydroxy-1,2,3,4-tetrahydro-benzo[f]-quinoline derivatives unexpectedly exhibit a selectivity, not hitherto found, of more than 1:1500 between the prodrug and the cytostatic agent on which the prodrug is based, combined at the same time with a high cytotoxicity of the cytostatic agent in the cell culture.